The hypothesis that neurochemical abnormalities are involved in schizophrenia
has a long history (Andreasen 1995). However, empirical evidence was provided
only when the mode of action of antipsychotic drugs was shown to be related
to catecholamine metabolism in the brain, and more specifically to blocking
the effect of these drugs on the catecholamine postsynaptic receptors
(Carlsson and Lindkvist 1963). Subsequent research indicated that it was
the capacity of antipsychotics to block the dopamine-2(D2) receptors that
was responsible for their clinical efficacy (Peroutka and Snyder 1980).
Dopamine increases the sensitivity of brain cells to stimuli. Ordinarily,
this heightened sensitivity is useful in increasing a person's awareness
in times of stress or danger. However, for a person with schizophrenia,
the addition of dopamine's effect to an already hyperactive brain state
may tip that person into a psychosis.
Additional support for the role of dopaminergic
hyperactivation in schizophrenia came from the observation that amphetamine,
a drug that increases dopamine's effects, worsens and may even elicit
schizophrenia-like symptoms (Meltzer and Stahl 1976). This increased dopaminergic
activity in the central nervous system occurs through two mechanisms:

increased availability of dopamine in synaptic sites and

receptor hypersensitivity.

Both these mechanisms have been extensively investigated in schizophrenia,
but conclusive evidence in favour of either is thus far lacking. Studies
of dopamine turn-over in patients' body fluids as well as direct determination
of dopamine levels in postmortem brain tissue have yielded conflicting
results (Heritch 1990; Hirsch and Weinberger 1995; Bloom and Kupfer 1995).
Neuroimaging techniques, such as PET, have
recently been applied to determine dopamine receptor density in the brain.
While the blocking effect of classical antipsychotics on dopamine receptors
has been clearly demonstrated, findings concerning dopamine-receptor density
in drug-free patients compared to controls vary considerably among researchers
(Wong et al. 1986; Farde et al. 1990). Using techniques of molecular biology,
an increased dopamine receptor density and sensitivity in postmortem brain
tissue of drug-free patients with schizophrenia have been demonstrated
(Seeman 1987, 1995; Stefanis et al. 1998). When the atypical antipsychotics
(clozapine, followed by risperidone, olanzapine, and others) were introduced,
researchers began to question the assumption that the D2 blocking effect
of antipsychotics was the major factor accounting for their antipsychotic
action. It has been demonstrated that the mode of action of the "atypical"
antipsychotics involves a close affinity for several receptors besides
the D2 dopamine receptors, including serotonin (5-HT) receptors. (Meltzer
et al 1996). Current research findings therefore suggest that many other
receptor sites, such as D1, D3, D4, 5-HT2, and NMDA, are also likely to
be involved in the pathogenesis of schizophrenia (Hirsch and Weinberger
1995; Seeman 1995; Kerwin et al. 1997).